2-heterocyclically substituted dihydropyrimidines

ABSTRACT

The invention relates to new 2-heterocyclically substituted dihydropyrimidines, medicaments which contain these 2-heterocyclically substituted dihydropyrimidines, and a process for preparation of medicaments. The invention furthermore relates to the use of the 2-heterocyclically substituted dihydropyrimidines for the production of a medicament, in particular for the treatment of acute or chronic viral diseases, in particular for the production of a medicament for the treatment of acute or chronic hepatitis B infections.

The present invention relates to new 2-heterocyclically substituteddihydropyrimidines, processes for their preparation and their use asmedicaments, in particular as medicaments for the treatment andprophylaxis of hepatitis B.

The publication EP 103 796 A2 has already disclosed dihydropyrimidineshaving an action affecting the circulation.

The present invention relates to new 2-heterocyclically substituteddihydropyrimidines of the general formula (I)

or its isomeric form (Ia)

in which

R¹ represents phenyl, furyl, thienyl, pyridyl, cycloalkyl having 3 to 6carbon atoms or a radical of the formula

 where the abovementioned ring systems are optionally monosubstituted orpolysubstituted in an identical or different manner by substituentsselected from the group consisting of halogen, trifluoromethyl, nitro,cyano, trifluoromethoxy, carboxyl, hydroxyl, (C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl and (C₁-C₆)-alkyl, which for its part can besubstituted by aryl having 6 to 10 carbon atoms or halogen,

and/or the ring systems mentioned are optionally substituted by groupsof the formula —S—R⁶, NR⁷R, CO—NR⁹R¹⁰, SO₂—CF₃ and —A—CH₂—R¹¹,

 in which

R⁶ denotes phenyl which is optionally substituted by halogen,

R⁷, R⁸, R⁹ and R¹⁰ are identical or different and denote hydrogen,phenyl, hydroxy-substituted phenyl, hydroxyl, (C₁-C₆)-acyl or(C₁-C₆)-alkyl, which for its part can be substituted by hydroxyl,(C₁-C₆)-alkoxycarbonyl, phenyl or hydroxy-substituted phenyl,

A denotes a radical O, S, SO or SO₂,

R¹¹ denotes phenyl which is optionally mono- to polysubstituted, in anidentical or different manner, by substituents selected from the groupconsisting of halogen, nitro, trifluoromethyl, (C₁-C₆)-alkyl and(C₁-C₆)-alkoxy,

R² represents a radical of the formula —OR¹² or —NR¹³R¹⁴,

 in which

R¹² denotes hydrogen, (C₁-C₆)-alkoxycarbonyl or a straight-chain,branched or cyclic, saturated or unsaturated (C₁-C₈)-hydrocarbon radicalwhich optionally contains one or two identical or different hetero chainmembers from the group consisting of O, CO, NH, —N—(C₁-C₄)-alkyl,—N—((C₁-C₄)-alkyl)₂, S and SO₂ and which is optionally substituted byhalogen, nitro, cyano, hydroxyl, aryl having 6 to 10 carbon atoms oraralkyl having 6 to 10 carbon atoms, heteroaryl or a group of theformula —NR¹⁵R¹⁶,

 in which

R¹⁵ and R¹⁶ are identical or different and denote hydrogen, benzyl or(C₁-C₆)-alkyl,

R¹³ and R¹⁴ are identical or different and denote hydrogen,(C₁-C₆)-alkyl or cycloalkyl having 3 to 6 carbon atoms,

R³ represents hydrogen, amino or

a radical of the formula

formyl, cyano or trifluoromethyl, or

a straight-chain, branched or cyclic, saturated or unsaturatedhydrocarbon radical having up to 8 carbon atoms, which is optionallymono- or polysubstituted, in an identical or different manner, byaryloxy having 6 to 10 carbon atoms, azido, cyano, hydroxyl, carboxyl,(C₁-C₆)-alkoxycarbonyl, a 5- to 7-membered heterocyclic ring,(C₁-C₆)-alkylthio, (C₁-C₆)-alkoxy, which for its part can be substitutedby azido or amino,

and/or is substituted by triazolyl which for its part can be substitutedup to 3 times by (C₁-C₆)-alkoxycarbonyl,

and/or can be substituted by groups of the formula —OSO₂—CH₃ or(CO)_(a)—NR¹⁷R¹⁸,

 in which

a denotes a number 0 or 1,

R¹⁷ and R¹⁸ are identical or different and denote hydrogen or aryl,aralkyl having 6 to 10 carbon atoms,

or denote (C₁-C₆)-alkyl which is optionally substituted by(C₁-C₆)-alkoxycarbonyl, hydroxyl, phenyl or benzyl, where phenyl orbenzyl are optionally mono- or polysubstituted, in an identical ordifferent manner, by hydroxyl, carboxyl (C₁-C₆)-alkyl or (C₁-C₆)-alkoxy,or (C₁-C₆)-alkyl is optionally substituted by groups of the formulaNH—CO—CH₃ or NH—CO—CF₃,

R⁴ represents hydrogen, (C₁-C₄)-alkyl, acetyl or benzoyl,

D represents an oxygen or sulphur atom,

R⁵ represents hydrogen, halogen or straight-chain or branched alkylhaving up to 6 carbon atoms,

and their salts.

Compounds of the general formulae (I) and (Ia) according to theinvention are preferred

in which

R¹ represents phenyl, furyl, thienyl, pyridyl, cyclopentyl orcyclohexyl, where the abovementioned ring systems are optionallysubstituted one or 2 times, in an identical or different manner, bysubstituents selected from the group consisting of halogen,trifluoromethyl, nitro, SO₂—CF₃, methyl, cyano, trifluoromethoxy,carboxyl, methoxycarbonyl or radicals of the formulae—CO—NH—CH₂—C(CH₃)₃, —CO—NH(CH₂)₂OH, —CO—NH—CH₂—C₆H₅, —CO—NH—C₆H₅,—CO—NH—(pOH)—C₆H₄, —O—CH₂—C₆H₅ or —S—pCl—C₆H₄,

R² represents a radical of the formula —OR² or —NR¹³R¹⁴,

 in which

R¹² denotes hydrogen, (C₁-C₄)-alkenyl or (C₁-C₄)-alkyl, which isoptionally substituted by pyridyl, cyano, phenoxy, benzyl or by aradical of the formula —NR¹⁵R¹⁶,

 in which

R¹⁵ and R¹⁶ are identical or different and denote hydrogen, methyl orethyl,

R¹³ and R¹⁴ are identical or different and denote hydrogen, methyl,ethyl or cyclopropyl,

R³ represents hydrogen or a radical of the formula

represents formyl, cyano, trifluoromethyl or cyclopropyl, or

represents (C₁-C₄)-alkyl which is optionally substituted by radicals ofthe formula —SO₂CH₃, —NH—CO—CH₃, —NH—CO—CF₃, fluorine, chlorine,(C₁-C₃)-alkoxycarbonyl or hydroxyl,

O and/or alkyl is optionally substituted by groups of the formula—OSO₂—CH₃ or (CO)_(a)—NR¹⁷R¹⁸,

 in which

a denotes a number 0 or 1,

R¹⁷ and R¹⁸ are identical or different and denote hydrogen, phenyl orbenzyl, or

denote C₁-C₄-alkyl which is optionally substituted by(C₁-C₄)-alkoxycarbonyl, hydroxyl, phenyl or benzyl, where phenyl orbenzyl are optionally mono- or polysubstituted, in an identical ordifferent manner, by hydroxyl, carboxyl, (C₁-C₄)-alkyl or(C₁-C₄)-alkoxy, and/or (C₁-C₄)-alkyl is optionally substituted byradicals of the formula —NH—CO—CH₃ or —NH—CO—CF₃, or

R⁴ represents hydrogen, methyl, ethyl or acetyl,

D represents an oxygen or sulphur atom,

R⁵ represents hydrogen, halogen or (C₁-C₄)-alkyl,

and their salts.

Compounds of the general formulae (I) and (Ia) according to theinvention are particularly preferred

in which

R¹ represents phenyl or thienyl, where the abovementioned ring systemsare optionally substituted up to 2 times, in an identical or differentmanner, by substituents selected from the group consisting of fluorine,chlorine, methyl, trifluoromethyl or nitro,

R² represents a radical of the formula —OR¹² or —NR¹³R¹⁴,

 in which

R¹² represents hydrogen or (C₁-C₄)-alkyl,

R¹³ and R¹⁴ are identical or different and denote hydrogen or methyl

R³ represents hydrogen or formyl, cyano, trifluoromethyl or cyclopropyl,or represents (C₁-C₃)-alkyl which is optionally substituted by fluorine,chlorine, hydroxyl, which for its part can be substituted up to 3 timesby C₁-C₃-alkoxycarbonyl,

R⁴ represents hydrogen or methyl,

D represents an oxygen or sulphur atom,

R⁵ represents hydrogen, fluorine, chlorine or (C₁-C₃)-alkyl,

and their salts.

Compounds of the general formulae (I) and (Ia) according to theinvention are very particularly preferred

in which

R¹ represents phenyl or thienyl, each of which is optionally substitutedup to 2 times, in an identical or different manner, by fluorine orchlorine,

R² represents methoxy, ethoxy or n-propoxy,

R³ represents hydrogen, methyl or cylcopropyl,

R⁴ represents hydrogen,

D represents an oxygen or sulphur atom,

R⁵ represents hydrogen, fluorine or chlorine,

and their salts.

In the context of the invention, cycloalkyl having 3 to 6 carbon atomsrepresents cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl. Thefollowing may be preferably mentioned: cyclopentyl or cyclohexyl.

Aryl in general represents an aromatic radical having 6 to 10 carbonatoms. Preferred aryl radicals are phenyl and naphthyl.

In the context of the invention, (C₁-C₆)-alkyl represents astraight-chain or branched acyl radical having 1 to 6 carbon atoms. Astraight-chain or branched acyl radical having 1 to 4 carbon atoms ispreferred. Preferred acyl radicals are acetyl and propionyl.

In the context of the invention, (C₁-C₆)-alkyl represents astraight-chain or branched alkyl radical having 1 to 6 carbon atoms. Astraight-chain or branched alkyl radical having 1 to 4 carbon atoms ispreferred.

The following may be mentioned as examples: methyl, ethyl, propyl,isopropyl, tert-butyl, n-pentyl and n-hexyl.

In the context of the invention, (C₂-C₆)-alkenyl represents astraight-chain or branched alkenyl radical having 2 to 6 carbon atoms. Astraight-chain or branched alkenyl radical having 3 to 5 carbon atoms ispreferred. Examples which may be mentioned are: ethenyl, propenyl,isopropenyl, tert-butenyl, n-pentenyl and n-hexenyl.

In the context of the invention, (C₁-C₆)-alkoxy represents astraight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Astraight-chain or branched alkoxy radical having 1 to 4 carbon atoms ispreferred. Examples which may be mentioned are: methoxy, ethoxy,propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

In the context of the invention, (C₁-C₆)-alkoxycarbonyl represents astraight-chain or branched alkoxycarbonyl radical having 1 to 6 carbonatoms. A straight-chain or branched alkoxycarbonyl radical having 1 to 4carbon atoms is preferred. Examples which may be mentioned are:methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

The compounds according to the invention can exist in stereoisomericforms which either behave as image and mirror image (enantiomers), orwhich do not behave as image and mirror image (diastereomers). Theinvention relates both to the enantiomers or diastereomers and to theirrespective mixtures. Like the diastereomers, the racemic forms can alsobe separated into the stereoisomerically uniform constituents in a knownmanner.

The substances according to the invention can also be present as salts.In the context of the invention, physiologically acceptable salts arepreferred.

Physiologically acceptable salts can be salts of the compounds accordingto the invention with inorganic or organic acids. Preferred salts arethose with inorganic acids such as, for example, hydrochloric acid,hydrobromic acid, phosphoric acid or sulphuric acid, or salts withorganic carboxylic or sulphonic acids such as, for example, acetic acid,maleic acid, fumaric acid, malic acid, citric acid, tartaric acid,lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonicacid, phenylsulphonic acid, toluenesulphonic acid ornaphthalenedisulphonic acid.

Physiologically acceptable salts can also be metal or ammonium salts ofthe compounds according to the invention. Particularly preferred saltsare, for example, sodium, potassium, magnesium or calcium salts, andalso ammonium salts, which are derived from ammonia, or from organicamines, such as, for example, ethylamine, di- or triethylamine, di- ortriethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine,lysine, ethylenediamine or 2-phenylethylamine.

The compounds of the general formula (I) or (Ia) according to theinvention can be prepared by a process

in which

[A] aldehydes of the general formula (II)

R¹—CHO  (II)

in which

R¹ has the meaning indicated above,

are reacted with amidines or their hydrochlorides of the formula (III)

in which

R⁵ and D have the meaning indicated above,

and compounds of the general formula (IV)

R³—CO—CH₂—CO—R²  (IV)

in which

R² and R³ have the meaning indicated above,

if appropriate in the presence of inert organic solvents with or withoutaddition of base or acid, or

[B] compounds of the general formula (V)

in which

R¹, R² and R³ have the meaning indicated above,

are reacted with amidines of the general formula (III)

in which

R⁵ and D have the meaning indicated above,

if appropriate in the presence of inert organic solvents at temperaturesbetween 20° C. and 150° C. with or without addition of base or acid, or

[C] aldehydes of the general formula (II)

R¹—CHO  (II)

in which

R¹ has the meaning indicated above,

are reacted with compounds of the general formula (VI)

in which

R² and R³ have the meaning indicated above,

and amidines of the general formula (III) as described above.

The processes according to the invention can be illustrated by way ofexample by the following reaction schemes:

For all process variants A, B and C, suitable solvents are all inertorganic solvents. These preferably include alcohols such as ethanol,methanol, isopropanol, ethers such as dioxane, diethyl ether,tetrahydrofuran, glycol monomethyl ether, glycol dimethyl ether orglacial acetic acid, dimethylformamide, dimethyl sulphoxide,acetonitrile, pyridine and hexarnethylphosphoramide.

The reaction temperatures can be varied within a relatively wide range.In general, the reaction is carried out between 20 and 150° C., butpreferably at the boiling temperature of the respective solvent.

The reaction can be carried out at normal pressure, but also at elevatedpressure. In general, the reaction is carried out under normal pressure.

The reaction can be carried out with or without addition of base oracid, but it has been shown that a reaction within the meaning of theinvention preferably takes place in the presence of relatively weakacids such as, for example, acetic acid or formic acid.

The aldehydes of the general formula (II) used as starting substancesare known or can be prepared according to methods known from theliterature [cf. T. D. Harris and G. P. Roth, J. Org. Chem. 44, 146(1979), German Offenlegungsschrift 2 165 260, July 1972, GermanOffenlegungsschrift 2 401 665, July 1974, Mijano et al., Chem. Abstr.59, (1963), 13 929 c, E. Adler and H.-D. Becker, Chem. Scand. 15, 849(1961), E. P. Papadopoulos, M. Mardin and Ch. Issidoridis, J. Org. Chem.Soc. 78, 2543 (1956)].

The amidines of the general formula (III) used as starting substancesare known in some cases or can be prepared according to methods knownfrom the literature [cf. Houben-Weyl, Methoden der organischen Chemie[Methods of organic chemistry], Vol. 11/2, page 38 ff (1958); R. L.Shoiner and F. W. Neumann, Chem. Review 35, 351 (1944)].

The β-ketocarboxylic acid esters of the general formula (IV) used asstarting substances are known or can be prepared according to methodsknown from the literature [e.g. D Borrmann, “Umsetzung von Diketen mitAlkoholen, Phenolen and Mercaptanen” [Reaction of diketene withalcohols, phenols and mercaptans], in Houben-Weyl, Methoden derorganischen Chemie [Methods of organic chemistry], Vol. VII/4, 230 ff(1968); Y. Oikawa, K. Sugano and 0. Yonemitsu, J. Org. Chem. 43, 2087(1978)].

The ylidene-β-ketoesters of the formula (V) used as starting substancescan be prepared by methods known from the literature [cf. G. Jones, “TheKnoevenagel Condensation”, in Organic Reactions, Vol. XV, 204 ff.(1967)].

The enaminocarboxylic acid esters of the formula (VI) used as startingsubstances are known or can be prepared by methods known from theliterature [cf. A. C. Cope, J. Am. Chem. Soc. 67, 1017 (1945)].

The antiviral action of the compounds according to the invention wasdetermined following the methods described by Sells et al. (M. A. Sells,M.-L. Chen, and G. Acs (1987) Proc. Natl. Acad. Sci. 84, 1005-1009) andKorba et al. (B. E. Korba and J. L. Gerin (1992) Antiviral Research 19,55-70).

The antiviral tests were carried out in 96-well microtitre plates. Thefirst vertical row of the plate contained only growth medium andHepG2.2.15 cells. It was used as a virus control.

Stock solutions of the test compounds (50 mM) were first dissolved inDMSO, further dilutions of the hepatitis B virus-producing HepG2.2.15cells were prepared in growth medium. As a rule, the compounds accordingto the invention were each pipetted into the second vertical test row ofthe microtitre plate in a test concentration of 100 μM (1st testconcentration) and then diluted 2¹⁰ times in steps of 2 in growth mediumplus 2% foetal calf serum (volume 25 μl).

Each well of the microtitre plate then contained 225 μl of a HepG2.2.15cell suspension (5×10 cells/ml) in growth medium plus 2% foetal calfserum.

The test mixture was incubated for 4 days, 37° Celsius, 5% CO₂.

The supernatant was then aspirated and discarded, and the wells received225 μl of freshly prepared growth medium. The compounds according to theinvention were each added again as a 10-fold concentrated solution in avolume of 25 μl. The mixtures were incubated for a further 4 days.

Before the harvesting of the supernatants to determine the antiviraleffect, the HepG2.2.15 cells were investigated for cytotoxic changes bylight microscopy or by means of biochemical detection procedures (e.g.Alamar Blue staining or Trypan Blue staining).

The supernatants were then harvested and absorbed by means of vacuum on96-well dot blot chambers covered with nylon membrane (according to themanufacturer's instructions).

Cytotoxicity Determination

Substance-induced cytotoxic or cytostatic changes in the HepG2.2.15cells were determined, for example, by light microscopy as changes inthe cell morphology. Substance-induced changes of this type in theHHepG2.2.15 cells in comparison with untreated cells were visible, forexample, as cell lysis, vacuolization or modified cell morphology. 50%toxicity (tox. 50) means that 50% of the cells have a morphologycomparable to the corresponding cell control.

The tolerability of some of the compounds according to the invention wasadditionally tested on other host cells such as, for example, HeLacells, primary peripheral human blood cells or transformed cell linessuch as H-9 cells. It was not possible to determine any cytotoxicchanges at concentrations of >10 μM of the compounds according to theinvention.

Determination of the Antiviral Action

In brief; after transfer of the supernatants to the nylon membrane ofthe dot blot apparatus (see above), the supernatants of the HepG2.2.15cells were denatured (1.5M NaCl/0.5N NaOH), neutralized (3M NaCl/0.5Mtris HCl, pH 7.5) and washed (2×SSC). The DNA was then baked onto themembrane by incubation of the filters at 120° C., 2-4 hours.

Hybridization of the DNA

As a rule, the detection of the viral DNA of the treated HepG2.2.15cells on the nylon filters was carried out using non-radioactive,digoxigenin-labelled hepatitis B-specific DNA probes, which in each casewere labelled according to the manufacturer's instructions, purified andemployed for hybridization.

Briefly: the prehybridization and hybridization was carried out in5×SSC, 1×blocking reagent, 0.1% N-lauroylsarcosine, 0.02% SDS and 100 μgof herring sperm DNA. Prehybridization was carried out for 30 minutes at60° C., specific hybridization using 20-40 ng/ml of the digoxigeninated,denatured HBV-specific DNA (14 hours. 60° C.). The filters were thenwashed.

Detection of the HBV DNA by Digoxigenin Antibodies

The immunological detection of the digoxigenin-labelled DNA was carriedout according to the manufacturer's instructions. Briefly: the filterswere washed and prehybridized in a blocking reagent (according to themanufacturer's instructions). Hybridization was then carried out with ananti-DIG antibody, which had been coupled to alkaline phosphatase. Aftera washing step, the substrate of the alkaline phosphatase, CSPD, wasadded and incubated with the filters for 5 minutes, which were thenwrapped in plastic film and incubated at 37° C. for a further 15minutes. The chemiluminescence of the hepatitis B-specific DNA signalswas visualized by means of exposure of the filters to an X-ray film(incubation depending on signal strength: 10 minutes to 2 hours). Thehalf-maximal inhibitory concentration (IC-50, inhibitory concentration50%) was determined as the concentration at which, compared with anuntreated sample, the hepatitis B-specific band was reduced by 50% bythe compound according to the invention.

The treatment of the hepatitis B virus-producing HepG2.2. 15 cells withthe compounds according to the invention surprisingly led to a reductionof viral DNA in the cell culture supernatant, which is expelled from thecells into the cell culture supernatant in the form of virions.

The compounds according to the invention exhibit a new, unforeseeableand valuable action against viruses. They are surprisingly antivirallyactive against hepatitis B (HBV) and are thus suitable for the treatmentof virus-induced diseases, in particular of acute and chronic persistentHBV virus infections. A chronic viral disease produced by HBV can leadto syndromes of differing severity; as is known, chronic hepatitis Bvirus infection in many cases leads to liver cirrhosis and/or tohepatocellular carcinoma.

Examples which may be mentioned of indication areas for the compoundsutilizable according to the invention are:

The treatment of acute and chronic viral infections which can lead toinfectious Hepatitis, for example infections with hepatitis B viruses.The treatment of chronic hepatitis B infections and the treatment ofacute hepatitis B viral infections are particularly preferred.

The present invention includes pharmaceutical preparations which, inaddition to non-toxic, inert pharmaceutically suitable excipients,comprise one or more compounds of the formulae (I) and (Ia) or whichconsist of one or more active compounds of the formula (I), andprocesses for the production of these preparations.

The active compounds of the formulae (I) and (Ia) should be present inthe abovementioned pharmaceutical preparations in a concentration ofapproximately 0.1 to 99.5% by weight, preferably of approximately 0.5 to95% by weight, of the total mixture.

Apart from the compounds of the formulae (I) and (Ia), theabovementioned pharmaceutical preparations can also comprise furtherpharmaceutical active compounds.

The abovementioned pharmaceutical preparations are prepared in acustomary manner by known methods, e.g. by mixing the active compound(s)with the excipient(s).

In general, it has proved advantageous both in human and in veterinarymedicine to administer the active compounds according to the inventionin total amounts of approximately 0.5 to approximately 500, preferably 1to 100, mg/kg of body weight every 24 hours, if appropriate in the formof a number of individual doses, to achieve the desired results. Anindividual dose contains the active compound(s) preferably in amountsfrom approximately 1 to 80, in particular 1 to 30, mg/kg of body weight.However, it may be necessary to depart from the doses mentioned, namelydepending on the species and the body weight of the subject to betreated, the nature and the severity of the disease, the type ofpreparation and the administration of the medicament, and the period orinterval within which administration takes place.

Starting Compounds

EXAMPLE I 2-Amidino-thiazole hydrochloride

4.5 g of sodium (0.2 mol) are added in portions to 220 ml of MeOH. Afterformation of the methoxide, 22.9 g (0.21 mol) of 2-cyano-thiazole (J.Chem. Soc. C, 1967, p. 517) are added and the mixture is stirred at RTfor two days. Inorganic salts are filtered off with suction, the mixtureis concentrated, the residue is crystallized using a little acetone andthe product is filtered off with suction. 17.4 g (51%)2-amidino-thiazole hydrochloride.

M.p.: 188° C., dec.

R_(f): 0.26 (EA/MeOH/H₂O/conc. NH₃=6:3:0.5:0.05)

PREPARATION EXAMPLES Example 1 Methyl4-(2-chlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

320 mg (2 mmol) of 2-amidino-thiazole hydrochloride, 470 mg (2 mmol) ofmethyl 2-chlorobenzylidene-acetoacetate and 100 mg (2.4 mmol) of sodiumacetate are refluxed for 16 h in 10 ml of ethanol. The mixture isconcentrated, rendered alkaline with dil. NaOH and extracted by shakingwith EA. After purification on silica gel (cyclohexane: EA=7:3), 350 mg(32%) of substance are obtained.

R_(f)=0.23 (cyclohexane/EA=7:3)

Example 2 Methyl4-(4-chlorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate

270 mg (1.7 mmol) of 2-amidino-thiazole, 200 mg (1.7 mmol) of methylacetoacetate, 230 mg (1.7 mmol) of 4-chlorobenzaldehyde and 165 mg (2mmol) of sodium acetate are refluxed for 16 h in 11 ml of ethanol.Work-up as in Example 1 affords 350 mg (31%) of amorphous substance.

R_(f)=0.20 (cyclohexane/EA=7:3)

The compounds shown in Table 1 are prepared analogously to the procedureof Example 2:

TABLE 1 Example No. Structure Yield R_(f)/m.p./[α]_(D) 3

34% 0.31 4

33% 0.33 5

23% 0.28 6 Preparation was carried out in 2-propanol.

36% 0.30/154° C. 7

27% 0.22 8

15% 0.28 9 (−)-Enantiomer of Example 6

Separation of 6 on chiral columns [α]_(D) = −52.0° (CH₃OH) 10 

0.33 (cyclohexane/ EA = 7:3) R_(f) = the distance of a substance fromthe starting point divided by the distance of the solvent front,likewise from the starting point M.p. = Melting point [α]_(D) ⁰ =Specific rotation EA = Ethyl acetate

What is claimed is:
 1. A dihydroxypyrimidine of the general formula (I)

or its isomeric form (Ia)

in which R¹ represents phenyl, furyl, thienyl, pyridyl, cycloalkylhaving 3 to 6 carbon atoms or a radical of the formula

 where the abovementioned ring systems are optionally monosubstituted orpolysubstituted in an identical or different manner, by substituentsselected from the group consisting of halogen, trifluoromethyl, nitro,cyano, trifluoromethoxy, carboxyl, hydroxyl, (C₁-C₆)-alkoxy,(C₁-C₆)-alkoxycarbonyl and (C₁-C₆)-alkyl, which for its part can besubstituted by aryl having 6 to 10 carbon atoms or halogen, and/or thering systems mentioned are optionally substituted by groups of theformula —S—R⁶, NR⁷R⁸, CO—NR⁹R¹⁰, SO₂—CF₃ and —A—CH₂—R¹¹,  in which R⁶ isphenyl which is optionally substituted by halogen, R⁷, R⁸, R⁹ and R¹⁰are identical or different and are hydrogen, phenyl, hydroxy-substitutedphenyl, hydroxyl, (C₁-C₆)-acyl or (C₁-C₆)-alkyl, which for its part canbe substituted by hydroxyl, (C₁-C₆)-alkoxycarbonyl, phenyl orhydroxy-substituted phenyl, A is a radical O, S, SO or SO₂, R¹¹ isphenyl which is optionally mono- to polysubstituted, in an identical ordifferent manner, by substituents selected from the group consisting ofhalogen, nitro, trifluoromethyl, (C₁-C₆)-alkyl and (C₁-C₆)-alkoxy, R²represents a radical of the formula —OR¹² or —NR¹³R¹⁴,  in which R¹² ishydrogen, (C₁-C₆)-alkoxycarbonyl or a straight-chain, branched orcyclic, saturated or unsaturated (C₁-C₈)-hydrocarbon radical whichoptionally contains one or two identical or different hetero chainmembers from the group consisting of O, CO, NH, —N—(C₁-C₄)-alkyl,—N—((C₁-C₄)-alkyl)₂, S and SO₂ and which is optionally substituted byhalogen, nitro, cyano, hydroxyl, aryl having 6 to 10 carbon atoms oraralkyl having 6 to 10 carbon atoms, or a group of the formula —NR¹⁵R¹⁶, in which R¹⁵ and R¹⁶ are identical or different and are hydrogen,benzyl or (C₁-C₆)-alkyl, R¹³ and R¹⁴ are identical or different and arehydrogen, (C₁-C₆)-alkyl or cycloalkyl having 3 to 6 carbon atoms, R³represents hydrogen, amino or a radical of the formula

formyl, cyano or trifluoromethyl, or a straight-chain, branched orcyclic, saturated or unsaturated hydrocarbon radical having up to 8carbon atoms, which is optionally mono- or polysubstituted, in anidentical or different manner, by aryloxy having 6 to 10 carbon atoms,azido, cyano, hydroxyl, carboxyl, (C₁-C₆)-alkoxycarbonyl,(C₁-C₆)-alkylthio, (C₁-C₆)-alkoxy, which for its part can be substitutedby azido or amino, and/or is substituted by triazolyl which for its partcan be substituted up to 3 times by (C₁-C₆)-alkoxycarbonyl, and/or canbe substituted by groups of the formula —OSO₂—CH₃ or (CO)_(a)—NR¹⁷R¹⁸, in which a is a number 0 or 1, R¹⁷ and R¹⁸ are identical or differentand are hydrogen or aryl, aralkyl having 6 to 10 carbon atoms, or are(C₁-C₆)-alkyl which is optionally substituted by (C₁-C₆)-alkoxycarbonyl,hydroxyl, phenyl or benzyl, where phenyl or benzyl are optionally mono-or polysubstituted, in an identical or different manner, by hydroxyl,carboxyl (C₁-C₆)-alkyl or (C₁-C₆)-alkoxy, NH—CO—CH₃ or NH—CO—CF₃, R⁴represents hydrogen, (C₁-C₄)-alkyl, acetyl or benzoyl, D represents anoxygen or sulphur atom, R⁵ represents hydrogen, halogen orstraight-chain or branched alkyl having up to 6 carbon atoms, or a saltthereof.
 2. A dihydropyrimidine according to claim 1, in which R¹represents phenyl, furyl, thienyl, pyridyl, cyclopentyl or cyclohexyl,where the abovementioned ring systems are optionally substituted one or2 times, in an identical or different manner, by substituents selectedfrom the group consisting of halogen, trifluoromethyl, nitro, SO₂—CF₃,methyl, cyano, trifluoromethoxy, carboxyl, methoxycarbonyl or radicalsof the formulae —CO—NH—CH₂—C(CH₃)₃, —CO—NH(CH₂)₂OH, —CO—NH—CH₂—C₆H₅,—CO—NH—C₆H₅, —O—CH₂—C₆H₅, —CO—NH—C₆H₄-pOH, or —S—C₆H₄-pCl; R² representsa radical of the formula —OR¹² or —NR¹³R¹⁴,  in which R¹² is hydrogen,(C₁-C₄)-alkenyl or (C₁-C₄)-alkyl, which is optionally substituted bycyano, benzyl or by a radical of the formula —NR¹⁵R¹⁶,  in which R¹⁵ andR¹⁶ are identical or different and are hydrogen, methyl or ethyl, R¹³and R¹⁴ are identical or different and are hydrogen, methyl, ethyl orcyclopropyl, R³ represents hydrogen or a radical of the formula

represents formyl, cyano, trifluoromethyl or cyclopropyl, or represents(C₁-C₄)-alkyl which is optionally substituted by radicals of the formula—SO₂CH₃, —NH—CO—CH₃, —NH—CO—CF₃, (C₁-C₃)-alkoxycarbonyl or hydroxyl,and/or alkyl is optionally substituted by groups of the formula—OSO₂—CH₃ or (CO)_(a)—NR¹⁷R¹⁸,  in which a is a number 0 or 1, R¹⁷ andR¹⁸ are identical or different and are hydrogen, phenyl or benzyl, orare C₁-C₄-alkyl which is optionally substituted by(C₁-C₄)-alkoxycarbonyl, hydroxyl, phenyl or benzyl, where phenyl orbenzyl are optionally mono- or polysubstituted, in an identical ordifferent manner, by hydroxyl, carboxyl, (C₁-C₄)-alkyl or(C₁-C₄)-alkoxy, —NH—CO—CH₃ or —NH—CO—CF₃, or R⁴ represents hydrogen,methyl, ethyl or acetyl, D represents an oxygen or sulphur atom, R⁵represents hydrogen, halogen or (C₁-C₄)-alkyl, or a salt thereof.
 3. Adihydropyrimidine according to claim 1 or 2, in which R¹ representsphenyl or thienyl, where the abovementioned ring systems are optionallysubstituted up to 2 times, in an identical or different manner, bysubstituents selected from the group consisting of fluorine, chlorine,methyl, trifluoromethyl or nitro, R² represents a radical of the formula—OR¹² or —NR¹³R¹⁴,  in which R¹² represents hydrogen or (C₁-C₄)-alkyl,R¹³ and R¹⁴ are identical or different and are hydrogen or methyl, R³represents hydrogen or formyl, cyano, trifluoromethyl or cyclopropyl, orrepresents (C₁-C₃)-alkyl which is optionally substituted by hydroxyl, R⁴represents hydrogen or methyl, D represents an oxygen or sulphur atom,R⁵ represents hydrogen, fluorine, chlorine or (C₁-C₃)-alkyl, or a saltthereof.
 4. A dihydropyrimidine according to claim 1, in which R¹represents phenyl or thienyl, each of which is optionally substituted upto 2 times, in an identical or different manner, by fluorine orchlorine, R² represents methoxy, ethoxy or n-propoxy, R³ representshydrogen, methyl or cylcopropyl, R⁴ represents hydrogen, D represents anoxygen or sulphur atom, R⁵ represents hydrogen, fluorine or chlorine ora salt thereof.
 5. A pharmaceutical composition, comprising at least onecompound of the general formula (I) or (Ia) according to claim 1 and apharmaceutically acceptable auxiliary or excipient.